ES2902874T3 - Chemical process for preparing imidazopyrrolidinone derivatives and their intermediates - Google Patents

Abstract

A process for preparing a compound of formula (D7), or a salt thereof, or a solvate thereof, **(See formula)** comprising the step of reacting a compound of formula (D6), or a salt thereof, or a solvate thereof, **(See formula)** in a solvent in the presence of base and a coupling agent, wherein the coupling agent is N,N'-carbonyldiimidazole.

Description

DESCRIPTION

Chemical process for preparing imidazopyrrolidinone derivatives and their intermediates

field of invention

FIELD OF DISCLOSURE

The present disclosure is in the field of organic synthesis and relates to novel intermediates and process steps useful for the preparation of imidazopyrrolidinone derivatives such as (6S)-5-(5-Chloro-1-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-(propan-2-yl)-5,6-dihydropyrrolo[3, 4-d]imidazol-4(1H)-one, or a cocrystal thereof, or a solvate including a hydrate thereof, and/or intermediates thereof.

DISCLOSURE BACKGROUND

The present disclosure relates to a process for the preparation of imidazopyrrolidinone derivatives and their derivatives.

More particularly, the present disclosure refers to a process for the preparation of the compound of formula (I)

also called (6S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5 -yl)-1-(propan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(H)-one, or a cocrystal thereof, or a solvate including a hydrate thereof itself, which are capable of inhibiting the interaction between the tumor suppressor protein p53 or variants thereof, and the MDM2 and/or MDM4 proteins, or variants thereof, respectively, especially binding to the MDM2 and/or MDM4 proteins, or variants thereof.

The p53 protein is known as a tumor suppressor protein that helps control cell integrity and prevents the proliferation of permanently damaged cells by initiating, among other responses, growth arrest or apoptosis (controlled cell death). p53 mediates its effects in that it is a transcription factor capable of regulating a series of genes that regulate, for example, the cell cycle and apoptosis. Therefore, p53 is an important cell cycle inhibitor. These activities are tightly controlled by MDM2, an important negative regulator of the p53 tumor suppressor. "MDM2" (originally from the oncogene "murine double minute 2") refers to both the name of the gene and the protein encoded by that gene. The MDM2 protein acts both as an E3 ubiquitin ligase that recognizes the W-terminal ^{transactivation domain} (tAd) ^{of tumor suppressor p53 and thus mediates ubiquitin-dependent degradation} of p53, and as an inhibitor of transcriptional activation of p53. p53.

The original mouse oncogene, encoding the MDM2 protein, was originally cloned from a transformed mouse cell line. The human homologue of this protein was later identified and is sometimes also referred to as HDM2 (for "human double minute 2"). Several types of human tumor and proliferative diseases have been shown to have increased levels of MDM2, including, but not limited to, soft tissue sarcomas, bone cancer, (eg, osteosarcomas), breast tumors, bladder cancer, Li syndrome. -Fraumeni, brain tumor, rhabdomyosarcoma and adrenocortical carcinoma and the like, further supporting the role of MDM2 as an oncogene. Another protein that belongs to the MDM2 family is MDM4, also known as MDMX.

Dysregulation of the MDM2/p53 ratio, for example due to mutations, polymorphisms or molecular defects in the affected cells, can therefore be found in many proliferative diseases. MDM2, in view of its mentioned effects, is capable of inhibiting the activity of the tumor suppressor protein p53, thus leading to the loss of the tumor suppressor activity of p53 and inhibiting the regulatory mechanisms that prevent uncontrolled cell proliferation. . As a consequence, uncontrolled proliferation may occur, leading to cancers such as tumors, leukemias or other proliferative diseases.

Imidazopyrrolidinone derivatives, such as the compound of formula (I), or a cocrystal thereof, or a solvate including a hydrate thereof, are described in WO2013/111105, in particular in examples 101 to 103. The compound of formula (I), called (6S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2, 4-dimethoxypyrimidin-5-yl)-1-(propan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(ÍH)-one, also known as SJ-5-(5-Chloro-1-methyl-2-oxo-1,2-d¡hydro-p¡r¡d¡n-3-¡l)-6-(4-chloro- fen¡l)-2-(2,4-d¡methoxy¡-p¡r¡m¡d¡n-5-¡l)-1-¡soprop¡l-5,6-d¡l'hydroíH- pyrrolo[3,4-d]m,dazol-4-one. These derivatives are capable of interfering with the interaction between p53 and MDM2 or, especially, oncogenic variants thereof, and thus allow p53 to exert its effect. Beneficial against uncontrolled tumor growth, allowing, for example, to accumulate, arrest the cell cycle and/or cause apoptosis of affected cells. Imdazoproldinone derivatives also show inhibition of MDM2/p53 and/or MDM4/p53 interaction (including this expression, in particular, the Hdm2/p53 and Hdm4/p53 interaction) and, in particular, a potent inhibition of the MDM2/p53 interaction. In particular, the derivatives act as inhibitors of the interaction of MDM2 with p53 by binding to MDM2, and/or act as inhibitors of the Interaction of MDM4 with p53 by binding to MDM4, making these derivatives useful in the treatment of a number of disorders, such as prostatic diseases ferat¡vas, especially cancer.

Chemical processes are usually carried out first on a small scale during the initial research/development phase. As development continues, the scale is successively increased to finally reach full size production scale in the last phase of development. After scaling up a process, issues related to process safety and efficiency become increasingly important. Failure to scale up properly can lead to loss of process control, accidents such as unexpected exothermic reactions (leakage reactions), hazards to health when handling large amounts of hazardous and/or toxic chemicals, environmental hazards, or uneconomical use of chemicals. Document WO2013/111105 describes the first processes for the preparation of imidazoproldinone derivatives developed during the research/investigation phase. lime. However, there remains a need to provide improved processes for the preparation of imidazopyrrolidine derivatives, such as the compound of formula ( I), or a cocrystal thereof, or a solvate including a hydrate thereof, and/or intermediates thereof, which are economically efficient and safe and suitable for the scale full size production.

The present disclosure relates to an improved synthesis of compound of formula (I), or a co-crystal thereof, or a solvate including a hydrate thereof, and its intermediates. using less hazardous chemicals and/or reaction conditions, generating less waste, and providing a reproducible process that is easier to handle at higher scale, a process that is more efficient and that generates better quality compounds.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows the X-ray powder diffraction pattern for the compound of formula (D9).

Figure 2 shows the X-ray powder diffraction pattern for the compound of formula (D10) L-malic acid.

Figures 3 to 7 show the proton NMR spectra of compounds D6, D7, D9, D10 and D14.

DISCLOSURE DESCRIPTION

Increasing the amount of reagents and solvents for the purpose of scaling up the processes described in WO2013/111105 to full size commercial production may be associated In addition to some risks such as loss of process control, unexpected exothermic reactions, accidents and safety problems while handling a large number of dangerous chemicals and/or or toxic.

Surprisingly, it was discovered that the modification of the process described in WO2013/111105 to synthesize the compound of formula (I), or a co-crystal thereof, or a solvate including a hydrate thereof, and synthetic intermediates in the manner described herein, provides a scalable method that can be safely scaled up with reproducible yields, less hazardous/toxic chemicals and produces less waste. In addition, this process produces better quality compounds more efficiently, at a lower cost. A summary of the process is shown in Scheme 1, see below.

Cyclation stage: D5->(D6)->D7

The present invention relates to a process for preparing a compound of formula (D7), or a salt thereof, or a solvate thereof,

comprising the step of reacting a compound of formula (D6), or a salt thereof, or a solvate thereof,

in a solvent in the presence of base and a coupling agent, wherein the coupling agent is N,N'-carbonyldiimidazole.

The process may be as defined in Scheme 2, comprising a two-step procedure including as a first step the reaction of a compound of formula (D5), or a salt thereof, or a solvate thereof, as described in WO2013/111105, to obtain a compound of formula (D6). In a second step, the compound of formula (D6), or a salt thereof, or a solvate thereof, is reacted in a solvent in the presence of base and a coupling agent to provide the compound of formula D7.

The reaction is preferably heated. Suitable solvents used for the reaction can be any polar solvent. For example, the solvent is one or more solvents selected from tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMAc), W-methyl-2-pyrrolidone (NMP), W-butyl-2-pyrrolidone, dichloromethane (DCM) , acetonitrile, ethanol, methanol, ethyl acetate, n-propanol, 2-propanol, n-butanol, 2-butanol, tert-butanol, and 2-methyltetrahydrofuran. The preferred solvent in this process is one or more solvents selected from tetrahydrofuran, dimethylformamide, dimethylacetamide, W-methyl-2-pyrrolidone, dichloromethane, acetonitrile, ethyl acetate, and ethanol. Much more preferably, the solvent is tetrahydrofuran.

The base used to carry out the reaction can be any base that a skilled person would select based on organic chemistry textbooks for this type of chemical transformation. The base can be, for example, potassium tert-butoxide (fBuOK), lithium bis(trimethylsilyl)amide (LiHMDS), sodium bis(trimethylsilyl)amide (NaHMDS), sodium methoxide (MeONa), potassium methoxide ( KOMe), sodium ethoxide (EtONa), potassium ethoxide (KOEt), sodium fert-butoxide (fBuONa), n-butyllithium (nBuLi), lithium di/sopropylamine (LDA), sodium carbonate (Na ² CO ³ ), potassium carbonate (K ² CO ³ ), cesium carbonate (CS ² CO ³ ), tribasic potassium phosphate (K ³ PO ⁴ ), tribasic sodium phosphate (Na ³ PO ⁴ ), N,N-di/sopropylethylamine (DIPEA), triethylamine (Et ³ N), sodium acetate (NaOAc), potassium acetate (KOAc), N-methylmorpholine (NMM), and 4-Dimethylaminopyridine (DMAP), or mixtures thereof. The preferred base in this process is one or more bases selected from fBuOK, ^LiHMDS , NaHMDS, MeONa, ^EtONa , ^fBuONa , n-BuLi, LDA, ^K2CO3 , ^Cs2CO3 , ^K3PO4 , DIPEA, NMM, DMAP, KOMe, KOEt and Et ³ N. Much more preferably, the reaction is carried out in the presence of fBuOK. The base may be present in an amount of between 0.01 and 0.5 equivalents. Preferably, the base may be present in a catalytic amount of between 0.05 and 0.2 equivalents. More preferably, the base may be present in a catalytic amount of about 0.1 equivalent.

The cyclization of compound (D6), or a salt thereof, as described in Scheme 2, is preferably carried out by stirring the reaction mixture for more than 2 hours, with tetrahydrofuran, potassium tert-butoxide and N,N- carbonyldiimidazole. Preferably, the reaction is carried out at a temperature between 50 and 80 °C, more preferably at a temperature between 60 and 70 °C. It is preferred to carry out the reaction in tetrahydrofuran, in the presence of a catalytic amount of base (for example, 0.05 to 0.2 equivalents) and in the presence of a coupling agent, since then the reaction is more efficient, the yield improved, the reaction results in fewer impurities and the risk of side reactions such as halogen exchange is reduced.

When referring to salts herein, it especially means pharmaceutically acceptable salts or other generally acceptable salts, unless excluded for chemical reasons, which will be readily understood by the skilled person. Salts with final or intermediate products may be formed when salt-forming groups, such as basic or acidic groups, are present, which may exist in at least partially dissociated form, for example, over a pH range of 4 to 10 in aqueous solutions, or they can be isolated in particular in solid, especially crystalline, form. Said salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds or any of the intermediates mentioned herein with a basic nitrogen atom (for example, imino or amino), especially the pharmaceutically acceptable salts. Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, lactic acid, fumaric acid, succinic acid, citric acid, amino acids, such as glutamic acid or aspartic acid. , maleic acid, hydroxymaleic acid, methylmaleic acid, benzoic acid, methane- or ethane-sulfonic acid, ethane-1,2-disulfonic acid, 1,5-naphthalene-disulfonic acid, 2-naphthalenesulfonic acid, benzenesulfonic acid, N- cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamic acid, or other organic protonic acids, such as ascorbic acid.

Coupling stage: D7+D8->D9

The invention optionally also includes a step of preparing a compound of formula (D9), or a salt thereof, or a solvate thereof, in a process comprising the step of reacting a compound of formula (D7), or a salt thereof, or a solvate thereof as shown in Scheme 3,

in a solvent in the presence of a metal catalyst, a base and optionally a ligand, wherein the solution of (D8) is added to a solution of (D7) over a period of 2 to 8 hours,

Preferably, the solution of (D8) is added over a period of 3 to 7 hours, preferably over a period of 4 to 6 hours. Much more preferably, the solution of (D8) is added over a period of 5 hours.

In general, the term "catalyst" refers to a catalytic amount of a chemical agent that enhances the rate of a chemical reaction by lowering the activation energy for the chemical reaction. The catalyst can be a heterogeneous catalyst or a homogeneous catalyst. The catalyst may generally be present in an amount of up to 10.0 mole %. Typically, the catalyst may be present in an amount of less than 6.0 mol%. The catalyst may further be present in a range of from about 0.005 mole % to about 5.0 mole %, from about 0.01 mole % to about 1.0 mole %, or from about 0. 0.5 mol% to about 0.5 mol%, based on starting material.

The term "heterogeneous catalyst" refers to a catalyst supported on a carrier, usually but not necessarily a substrate composed of an inorganic material, eg, a porous material such as carbon, silicon, and/or aluminum oxide. The term "homogeneous catalyst" refers to a catalyst that is not supported on a carrier.

The catalyst used to carry out the reaction outlined in Scheme 3 can be any metal catalyst that a skilled person would select based on organic chemistry textbooks for Suzuki coupling reactions. The metal catalyst, for example, may be selected from the group consisting of Pd(PPh3)2Cl2, Pd(PPh3)4, Pd(dba) ² , Pd2(dba)3, PdCl ² , palladium(II) acetate (Pd (OAc) ² ), [Pd(allyl)Cl] ² , Pd(dppf)Cl ² , PdBr2(PtBu3)2, Pd (crotyl)(PtBu3)Cl, Pd(PtBu3)2, Pd(Amphos) ² Cl ² , Pd(allyl)(Amphos)Cl, Pd(Binap)Br ² , Pd(dcpp)Cl ² , Pd(DiPrPF)Cl ² , Pd-PEPPSI-IPr, Chloro(2-dicyclohexylphosphino-2,,4,,6 ,-tri/'sopropyl-1,1,-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(M) (also known as XPhos 1st Generation Precatalyst), Chloro-(2-dicyclohexylphosphino-2, ,4,,6f-tri/sopropyl-1, 1 -biphenyl)[2-(2-amino-1, 1 -biphenyl)] palladium(II) (also known as XPhos 2nd Generation Precatalyst), Chlorine(2- dicyclohexylphosphino-2',6-dimethoxy-1,1-biphenyl)[2-(2-aminoethylphenyl)]palladium(N) (also known as SPhos 1st Generation Precatalyst), Chloro(2-dicyclohexylphosphino-2',6- dimethoxM,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(N) (also known as XPhos 2nd Generation Precatalyst), Cl Gold(2-dicyclohexylphosphino-2l,6l-diisopropoxy-1,1-biphenyl)[2-(2-aminoethylphenyl)]palladium(N) (also known as RuPhos 1st Generation Precatalyst), Chloro(2-dicyclohexylphosphino-2' ,6-diisopropoxM,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(N) (also known as RuPhos 2nd Generation Precatalyst), Pd/C, Pd, Ni(acac) ² , NiCl ² , Ni(PPh3)2Cl2, Ni(cod) ² , Ni(dppf)(cod), Ni(dppf)(cinnamyl), Ni(dppf) ² , Ni(dppf)Cl ² , Ni(dppp)Cl ² , Ni(PCy3)2Cl2, Ni(dppe)Cl ² , [1,1-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(N) (Pd(dtbpf)Cb), 1,1-Bis( di-/sopropylphosphino)ferrocene palladium (Pd(dippf)Cl ² ) or mixtures thereof. The preferred metal catalyst in this process is one or more than one palladium catalyst selected from [1,1-Bis(di-tertbutylphosphino)ferrocene]dichloropalladium(II) (Pd(dtbpf)Cl ² ), 1,1- Bis(di-/sopropylphosphino)ferrocene palladium (Pd(dippf)Cl ² ), [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(N) Pd(dppf)Cl ² and Pd(OAc) ² . Much more preferably, the metal catalyst is [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(N) (Pd(dppf)Cb). The catalyst may be present in an amount of between 0.1 and 6 mol%. Preferably, the metal catalyst is present in an amount of between 4 and 6 mol%. Much more preferably, the amount is about 5 mol%.

The reaction described in Scheme 3 can also be carried out in the presence of a ligand. Preferably, the reaction is carried out in the presence of a ligand. The term "ligand" means any compound, achiral or chiral, that can form a complex with a transition metal. The ligand used to perform the reaction is any ligand that a skilled person would select based on organic chemistry textbooks for Suzuki coupling reactions. The ligand may be one or more ligands selected from the group of PPh ³ , P(oTol) ³ , P(oTol)Ph ² , P(pTol) ³ , PfBu ³ , PfBu ³ *HBF ⁴ , PCy ³ , PCy ³ * HBF ⁴ , P(O/Pr) ³ , DPE-Phos, dppf, dppe, dppp, dcpp, dppb, P(Furyl) ³ , CPhos, sPhos, RuPhos, XPhos, DavePhos, JohnPhos and Xantphos. The ligand may be present in a range of about 2% mole to about 10 mole %. Preferably, the ligand is present in an amount of about 5 mol%.

The base used to perform the reaction described in Scheme 3 is any base that a skilled person would select based on organic chemistry textbooks for Suzuki coupling reactions. The base can be, for example, sodium carbonate (Na ² CO ³ ), potassium carbonate (K ² CO ³ ), cesium carbonate (Cs ² CO ³ ), thallium(I) carbonate (Tl ² CO ³ ) , sodium bicarbonate (NaHCO ³ ), potassium bicarbonate (KHCO ³ ), sodium acetate (NaOAc), potassium acetate (KOAc), sodium phosphate (Na ³ PO ⁴ ), potassium phosphate (K ³ PO ⁴ ) , lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH), cesium hydroxide (CsOH), barium hydroxide (Ba(OH) ² ), sodium methoxide (NaOMe), potassium methoxide (KOMe), sodium ethoxide (NaOEt), potassium ethoxide (KOEt), thallium ethoxide (TlOEt), sodium phenoxide (NaOPh), trimethylamine (Et ³ N), N,N-di/sopropylethylamine (DIPEA), sodium tert-butoxide (NaOfBu), potassium tert-butoxide (KOfBu), potassium fluoride (KF), and cesium fluoride (CsF), or mixtures thereof. The preferred base in this process is one or more bases selected from KF, K ³ PO ⁴ , NaOH and KHCO ³ . Much more preferably, the reaction is carried out in the presence of KF.

The reaction described in Scheme 3 can be carried out in a solvent selected from, for example, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, acetonitrile, toluene, dimethylformamide, dimethylacetamide, dimethylsulfoxide, dimethoxyethane, dichloromethane, acetone, N-methyl- 2-pyrrolidone, N-butyl-2-pyrrolidone, dimethyl carbonate, ethyl acetate, /sopropyl acetate, tert-butyl acetate, pentane, hexane, heptane, anisole, pyridine, triethylamine, water, methanol, ethanol, n -propanol, 2-propanol, n-butanol, 2-butanol, /so-propanol, tert-butanol and butanone, or mixtures thereof. The preferred solvent in this process is one or more solvents selected from 1,4-dioxane, water, dimethoxyethane, n-butyl-2-pyrrolidone, and butanone. Much more preferably, the solvent is a mixture of 1,4-dioxane and water. The ratio (volume to volume) of said mixture may be in the range of 20:1 to 1:20, preferably the ratio is such that there is an excess of 1,4-dioxane over water, for example the ratio is in range from 20:1 to 5:1, preferably the ratio is from 15:1 to 10:1.

The reaction described in Scheme 3 is advantageously carried out when the solvent is a mixture of 1,4-dioxane and water (for example, in a ratio of 15:1 to 10:1), the base is potassium fluoride (KF) , the palladium catalyst is [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cb), the boronic acid is (D8). Preferably, the reaction is carried out at a temperature between 80 and 180 °C, more preferably between 100 and 120 °C. Much more preferably, the reaction is carried out at 110 °C. Carrying out the reaction under these conditions is particularly advantageous, since the reaction is very efficient, the yield is improved and the generation of by-products is reduced.

X-ray diffraction (XRPD) of the substantially pure compound (D9) exhibits one or more, preferably at least 2 to 5, more preferably all, diffraction peaks having maxima at diffraction angles selected from 9.34°, 13.19°, 14.67°, 16.35°, 17.18°, 17.82°, 18.71°, 21.95°, 23.89°, 24.97°, 25.84° ( degrees 20, K of copper alpha 1), as shown in Figure 1. More preferably, the XRPD of compound (D9) exhibits one or more, preferably 2 to 4, more preferably all, diffraction peaks having maxima at diffraction angles selected from 9.34°, 14.67°, 17.18°, 21.95°, 23.89°, 25.84° (20 degrees, alpha 1 copper K). XRPD maximum values (in degrees) generally mean ±0.3°, more preferably ±0.2°, and most preferably ±0.1° of the given value.

The term "substantially pure" means that more than 80% of a crystalline form of a compound, or salt thereof, or co-crystal, as described herein, is present or isolated, preferably at least 85%, more preferably at least 90% and most preferably at least 95% of one of the crystalline forms described herein is present or isolated.

Separation of stereoisomers and preparation of the compound (D10)

The invention optionally also includes a step of preparing a compound of formula (D10) as described in Reaction Scheme 4, comprising the step of reacting a compound of formula (D9), or a salt thereof, or a solvate thereof, in a solvent with an acid to obtain a mixture of compound of formula (D14), or a salt, co-crystal, or solvate thereof, and compound of formula (D10) as described herein. The compound of formula (D10) as described herein and in Scheme 4 is a mixture of two compounds: an imidazopyrrolidinone derivative and an acid. The compound of formula (D10) may be in the form of a salt, a complex, a hydrate, a solvate, a polymorph, a co-crystal or a mixture thereof. Preferably, the compound of formula (D10) is in the form of a co-crystal.

The invention optionally also includes a step of preparing a compound of formula (D10), as described herein, comprising the steps of dissolving a compound of formula (D9), or a salt thereof, or a solvate thereof, in a solvent with an acid to obtain a mixture of compound of formula (D14), or salt thereof, or solvate thereof and compound of formula (D10) as described herein. During separation, one of the stereoisomers precipitates out of solution in a compound form (D10) as described herein, while the second stereoisomer remains in solution.

The process, as described in Scheme 4, is preferably carried out with one or more acids selected from L-malic acid, lactic acid, tartaric acid and malonic acid. More preferably, the acid is L-malic acid. L-malic acid is also called L-(— )-malic acid, (S)-(— )-2-hydroxysuccinic acid, or L-hydroxybutanedioic acid. The separation described in Scheme 4 is preferably carried out in one or more solvents selected from, for example, ethyl acetate, isopropyl acetate, butyl acetate, and propyl acetate. More preferably, the solvent is ethyl acetate.

Separation of the (D14) and (D10) stereoisomers as described in the scheme below is very efficient, improves the yield of the compound of formula (D10) as described herein, and improves the overall cost of the synthesis.

Scheme 4

The term "stereoisomers" means one of the absolute configurations of an individual organic molecule having at least one asymmetric carbon. Furthermore, as used herein, the term refers to any of the various stereoisomeric configurations that may exist for a given compound of the present disclosure and includes geometric isomers. It is understood that a substituent may be attached to a chiral center of a carbon atom. Therefore, the disclosure includes enantiomers, diastereomers, or racemates of the compound. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term is used to designate a racemic mixture where appropriate. "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each of the chiral carbons can be specified as either R or S. Resolved compounds, whose absolute configuration is unknown, can be designated (+) or (-) depending on the direction (right-handed or left-handed) in which they deviate the plane of polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers or axes and thus may give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of their absolute stereochemistry, as (R) or (S) . The present disclosure is intended to include all such possible isomers, including racemic mixtures, optically pure forms, and mixtures of intermediates.

To further increase the yield of the compound of formula (D10), as described herein, the process for preparing compound (D10) may optionally comprise the additional steps of reacting (D14), or a salt, co-crystal, or a solvate thereof, to obtain a compound of formula (D9), or a salt thereof, or a solvate thereof. The compound of formula (D9) can be obtained by dissolving compound of formula (D14) in one or more polar protic solvents selected from, for example, formic acid, 1-pentanol, 2-pentanol, 3-pentanol, 1-hexanol, n- butanol, /sopropanol, ethanol, methanol, acetic acid and water. Preferably, the solvent is methanol. The The reaction can be carried out in the presence of a base selected from, for example, sodium bicarbonate (NaHCO ³ ), sodium hydroxide (NaOH), potassium bicarbonate (KHCO ³ ), and potassium hydroxide (KOH). Preferably, the base is sodium bicarbonate (NaHCO ³ ). Preferably, the reaction is carried out at a temperature between 50 and 80 °C, more preferably between 55 and 75 °C. Much more preferably, the reaction is carried out at about 65°C. Carrying out the reaction under these conditions is advantageous since it is very efficient, improves yield and reduces the generation of by-products.

Then, the newly formed compound of formula (D9) or a salt thereof, or a solvate thereof, is reacted in a solvent in the presence of an acid to obtain a mixture of compound (D10), as described herein , and compound (D14) in the same way as above. Optionally, the transformation of compound (D14) to compound (D10) via compound (D9), as described in Scheme 4, may be repeated one or more times, preferably the transformation is repeated at least once.

Yet another aspect of the present disclosure relates to compound (D10), wherein the acid is selected from L-malic acid, lactic acid, tartaric acid and malonic acid. Preferably the acid is L-malic acid. Another aspect of the present disclosure refers to the compound (D10) obtained or obtainable by the process shown in Scheme 4, where the acid is selected from L-malic acid, lactic acid, tartaric acid and malonic acid. Preferably the acid is L-malic acid.

Preferably, the compound of D10 is obtained as a crystalline material. X-ray powder diffraction (XRPD) of the substantially pure crystalline material of compound of formula (D10) L-malic acid shows one or more, preferably at least two to four, more preferably all, diffraction peaks having maxima at selected diffraction angles between 9.49°, 10.64°, 14.23°, 16.23°, 17.16°, 17.45°, 19.75°, 20.18°, 21.02° , 21.42°, 21.97°, 22.39°, 22.91°, 23.98°, 24.15°, 24.80°, 25.04°, 25.85°, 26.11° , 27.21°, 28.18° (degrees 20, K of copper alpha 1) as also shown in Figure 2. Much more preferably, the XRPD of the compound of formula (D10) L-malic acid has one or more , preferably at least two to four, more preferably all diffraction peaks having maxima at diffraction angles selected from 9.49°, 14.23°, 16.23°, 17.16°, 21.02°, 21.42°, 22.39°, 24.80°, 25.04°, 27.21° (20 degrees, alpha 1 copper K). XRPD maximum values (in degrees) generally mean within ±0.3°, more preferably within ±0.2°, and most preferably within ±0.1° of the given value.

Compound (D10) L-malic acid also has a melting point (mp) of 188 ±1 °C (start, by DSC).

The term "co-crystal" refers to a crystalline entity in which more than one molecular substance is incorporated into the unit cell, and both or all of the molecular components are solid at room temperature and pressure, each containing distinctive physical characteristics, such as structure, melting point, and heats of fusion. Cocrystals are generally crystalline materials composed of two or more molecules in the same crystal lattice. The co-crystals may be composed of an active pharmaceutical ingredient (API) with a neutral host compound (also called a conformer) in a crystal lattice. When the API and co-crystal former are in a neutral state and can build or join through non-ionic interactions, hydrogen bonds (a non-covalent bond is formed between a hydrogen bond donor on one of the moieties and a hydrogen bond acceptor of the other), n-stacking, host-host complex formation, and Van der Waals interactions. Various properties of a pharmaceutical composition can affect the initiation of solid state nucleation or precipitation of the API. Such properties include the identity or quantity of the excipient and the identity or quantity of the pharmaceutical compound in the composition. Other properties may include the amount of other diluents or carriers, such as salts or buffering compounds. The pharmaceutical compound itself can be screened in a variety of different ways if it is susceptible to polymorphism. Additionally, according to the disclosure, different salts, solvates, hydrates, co-crystals and other forms of the API can be screened. In general, the API is normally capable of existing as a supersaturated solution, preferably in an aqueous based medium. The API may be a free acid, or a free base, or a co-crystal, or a salt, or a solvate, or a hydrate or dehydrate thereof.

Formation of a compound of formula (I), or a solvate including a hydrate of the same, or a co-crystal of the same.

The invention optionally also includes a step of preparing a compound of formula (I), or a solvate including a hydrate thereof, or a co-crystal thereof, as described in Scheme 5.

The reaction to form intermediate (D11), or a salt thereof, or a solvate thereof, or a cocrystal thereof as described in Scheme 5 may be carried out in a solvent selected from, for example, dichloromethane, ethanol, acetate ethyl, /sopropyl acetate and water, in the presence of an alcohol. Preferably, the reaction is carried out in ethanol, ethyl acetate and water, in the presence of ethanol. The reaction to form intermediate (D11), or a salt thereof, or a solvate thereof, or a cocrystal thereof is preferably carried out at a temperature between 30 and 70 °C, more preferably at a temperature between 40 and 60 °C, much more preferably at a temperature of 50 °C.

Intermediate (D11), or a salt thereof, or a solvate thereof, or a co-crystal thereof, is then transformed into a compound of formula (I), or a solvate thereof, or a co-crystal thereof, as it is described in Scheme 5. The reaction is preferably carried out in a solvent selected from, for example, water, acetone, methanol, ethanol, /sopropanol and n-butanol, or a mixture thereof. More preferably, the reaction is carried out in water and acetone, or a mixture thereof. The compound of formula (I) is preferably obtained in substantially pure crystalline form.

The invention optionally also includes the step of forming a substantially pure crystalline form of the compound of formula (I). The substantially pure crystalline form of the compound of formula (I) can be obtained by spontaneous crystallization of the compound of formula (I). The present disclosure also refers to the formation of the substantially pure crystalline form of the compound of formula (I) by the addition of a seed, that is, a small amount of the crystalline form of the compound of formula (I) obtained by spontaneous crystallization , as described above, (1% by weight or less, called seed) to, for example, a suspension, a solution, a mixture or a dispersion, to enhance crystallization. The temperature usefully employed for seeding ranges from 20 to 40°C, more preferably at a temperature of 25°C. As used herein, the term "seed" may be used as a noun to describe one or more crystals of a crystalline compound of formula (I). The term "seed" may also be used as a verb to describe the act of introducing said one or more crystals of a crystalline compound of formula (I) into an environment (including, but not limited to, for example, a solution, a mixture, a suspension or a dispersion) thereby resulting in the formation of more crystals of the crystalline compound of formula (I).

The invention comprises a process for preparing a compound of formula (I), or a solvate including a hydrate thereof, or a cocrystal thereof, the process comprising the steps of: preparing a compound of formula (D7), or a salt thereof itself, or a solvate thereof, according to claim 1 and as described in Scheme 2 and reacting the compound of formula (D7) obtained, or a salt thereof, or a solvate thereof, with a compound ( D8) as described in Scheme 3 to obtain a compound of formula (D9), or a salt thereof, or a co-crystal thereof. A compound of formula (D10) as defined herein and described in Scheme 4 is then prepared, and finally the compound of formula (D10), defined herein, is reacted as described in Scheme 5 to obtain a compound of formula (I), or a solvate including a hydrate thereof, or a co-crystal thereof. Preferably, the compound of formula (I) is prepared in its hydrate form, which is referred to herein as (D12).

ABBREVIATIONS

Ac Acetyl

acac Acetylacetone

Amphos Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)

AOP 7-azabenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate

API Active pharmaceutical ingredient

BEP 2-bromo-1-ethyl-pyridinium tetrafluoroborate

BINAP (1,1'-Binaphthalene-2,2'-diyl)bis(diphenylphosphine)

BOP Tri(dimethylamino)benzotriazol-1-yloxyphosphonium hexafluorophosphate

BTFFH Bis(tetramethylene)fluoroformidinium hexafluorophosphate

CDI NN'-Carbonyldiimidazole

CMDT 2-Chloro-4,6-dimethoxy-1,3,5-triazine

cod Cyclo-1,5-octadiene

cy Cyclohexyl

dba 1,4-Bis(diphenylphosphino)butane

DCC NN-Dicyclohexylcarbodiimide

DCM Dichloromethane

dcpp 1,3- Bis(dicyclohexylphosphanyl)propane

DIPA Di/sopropylamine

DIPEA N,N-di/sopropylethylamine

DMAc Dimethylacetamide

DMAP 4-Dimethylaminopyridine

DMF N,N-dimethylformamide

DMTMM 4-(4,6-dimethoxy-1,3,5-tri azin-2-yl)-4-methylmorpholinium chloride

Dppb 1.4- Bis(diphenylphosphino)butane

dppe 1.2- Bis(diphenylphosphino)ethane

dppf 1,1'-bis(diphenylphosphanyl)ferrocene

dppp 1.3- Bis(diphenylphosphanyl)propane

EDC N-Ethyl-W-(3-dimethylaminopropyl)carbodiimide

eq. Equivalent

Et ³ N Triethylamine

EtONa/EtOK Sodium ethoxide/Potassium ethoxide

g Gram(s)

Ghosez's reagent 1-Chloro-N,N,2-trimethylpropenylamine

h Hour(s)

HATU N,N,N',N'-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate HBTU N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1 hexafluorophosphate -il)uronium HDM2 Double human minute 2

HOBt hydroxybenzotriazole

HPLC High Performance Liquid Chromatography

IBCF Isobutyl Carbonochloridate

K ² CO ³ /Na ² CO ³ Potassium carbonate/sodium carbonate

K ^s PO ⁴ /Na ³ PO ⁴ Tribasic Potassium Phosphate/Tribasic Sodium Phosphate

KF Potassium fluoride

KHCO ³ /NaHCO ³ Potassium hydrogen carbonate/Sodium hydrogen carbonate

LDA Lithium Di/Sopropylamine

LiHMDS Lithium bis(trimethylsilyl)amide

MDM2 Murine Double Minute 2

MeONa Sodium methoxide

mg/mL Milligram(s)/Milliliter(s)

mole Mol(s)

MS ² O Methanesulfonic Anhydride

NaHMDS Sodium bis(trimethylsilyl)amide

NaOH Sodium hydroxide

n-BuLi n-Butyl-lithium

NMM N-methylmorpholine

NMR Nuclear Magnetic Resonance Spectroscopy

Pd(OAc) ² Palladium(II) acetate

Pd/C Palladium on carbon

Pd ² (dba) ³ Tris(dibenzylideneacetone)dipalladium(0)

Pd(dippf)Cl ² 1,1'-bis(di/sopropylphosphino)ferrocene palladium dichloride

Pd(dppf)Cl ² 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride

Pd(dtbpf)Cl ² [1,1'-Bis(di-fert-butylphosphino)ferrocene]dichloropalladium(N)

Pd(dtbpf)Cl ² [1,1'-Bis(di-fert-butylphosphino)ferrocene]dichloropalladium(N)

Pd-PEPPSI-iPr [1,3-bis(2,6-di/sopropylphenyl)imidazol-2-idylene](3-chloropyridyl)palladium(N) dichloride PEPPSI Stabilization and initiation of preparation of pyridine-enhanced Phos precatalysts phosphine

POBr ³ phosphoryl bromide

POCl ³ Phosphoryl chloride

PyBOP Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate

T °C Temperature in degrees Celsius

T3P 2,4,6-Tripropyl-1,3,5,2,4,6-Trioxatriphosphorinane-2,4,6-Trioxide

TAD Transactivation domain

fBuOK ferc-Potassium butoxide

fBuONa fert-Butoxide sodium

TFFH Fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate

THF Tetrahydrofuran

EXAMPLES

The following examples are merely illustrative of the present disclosure and should not be construed as limiting the scope of the invention which is defined by the appended claims.

Synthesis

In general, compounds according to the present disclosure can be synthesized by the route described in Schemes 1-5 as shown herein.

The skilled artisan will appreciate that the general synthetic pathways detailed above show common reactions to convert starting materials as needed. Where specific reactions are not provided, the skilled person will know that such reactions are well known to those skilled in the art and appropriate conditions are believed to be within the common general knowledge of the skilled person. The starting materials are commercially available compounds or are known compounds and can be prepared by procedures described in the art of organic chemistry.

The compounds described herein, in free form, can be converted to salt form, and vice versa, in a conventional manner understood by those skilled in the art. The compounds in free or salt form can be obtained in the form of hydrates or solvates containing a solvent used for crystallization. The compounds described herein can be recovered from the reaction mixtures and purified in conventional manner. Isomers, such as stereoisomers, can be obtained in a conventional manner, eg, by fractional crystallization or asymmetric synthesis from correspondingly substituted, eg, optically active, asymmetrically substituted starting materials. The various starting materials, intermediates and compounds of the preferred embodiments can be isolated and purified, where appropriate, using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation and chromatography. Unless otherwise indicated, salts can be prepared from the compounds by known salt-forming procedures.

The compounds described herein can be prepared, for example, using the reactions and techniques described below and in the examples. The reactions can be carried out in an appropriate solvent for the reagents and materials used and suitable for the transformations that are carried out. Those skilled in the art of organic synthesis will understand that the functionality present on the molecule should be consistent with the proposed transformations. This will sometimes require judgment to modify the order of synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the disclosure.

It will be understood by those skilled in the art that the reactions were first run on a small scale to see if the starting materials could be reacted in high yields and high purities before being scaled up. The desired compounds obtained during said small-scale reaction, which spontaneously crystallized, were used to enhance the latter reactions, using the "seeding" technique. In this case, below about 1% by weight or less of seed crystals were added, if necessary, to the reaction mixture to more rapidly generate spontaneous crystallization of the desired product.

Measurement methods

- Proton NMR analyzes were performed using a Bruker 400 NMR machine.

- XRPD was measured using a Panalytical x-pert Pro and/or a Bruker D8 advanced. The amount of sample used for the measurement was between 20-200 mg. The sample preparation technique used was a Kapton sheet coated with stirring oil and the sample was held using a transmission sample holder: unidirectional clamping system for the internal parts and a metal ring for the external part. Measurement conditions were as follows: oscillation 0.3 sec/step, measurement time: time per step 0.017, voltage kV40/mV40. The wavelength used was copper alpha1 K radiation. The compound used for calibration was corundum [a-AhO3]. The measurement error is ±0.2 theta.

Note that different samples of a particular crystal form will share the same major X-ray powder diffraction (XRPD) peaks, but that there may be variation in powder patterns with respect to minor peaks.

- The melting point was measured using the Mettler Toledo DSC821e with Ceramic FRS5 Sensor. The purge gas was N ² ; 40 |jl gold plated crucibles (high pressure). Measurement conditions: heating rate 4.0 K/min.

Example 1: Cyclization stage (D5->D6->D7)

Process stage D5->D6

A suspension of compound D5 (60 g), solid NaOH (5.3 g, 1.2 eq) in water 180 g and ethanol 370 g was heated to reflux and stirred for more than 2 hours. After conversion to D6, 3.1 wt% aqueous HBr (385 g, 1.35 eq) was added slowly to the reaction mixture over 1 hour at reflux. The resulting suspension was stirred at reflux for an additional 0.5 hour, cooled at 25°C over 6 hours, and stirred at 25°C for 8 hours. The suspension was filtered, washed with 50% ethanol solution and dried in vacuo at 60 °C to give compound D6 as a white solid (54.1 g, 95% yield, 1H- NMR, 400 MHz, CDCl3: see Figure 3).

Process stage D6->D7

A suspension containing compound D6 (70g) in 840g tetrahydrofuran (THF) was heated to 35-45°C. N,W-Carbonyldiimidazole (CDI, 1.2 eq., 26.5 g) was then added in portions. The mixture was then heated to 60-70°C and stirred for more than 1 hour. After conversion to the active intermediate, the reaction mixture was cooled to 55-60°C, followed by the slow addition of a 6% solution of potassium tert-butoxide in THF (0.1 eq.). The mixture was heated again to 60-70°C and stirred for more than 2 hours until the sum of compound D6 and intermediate was less than 3%. The reaction mixture was then cooled to 25°C and quenched by the addition of water (0.5 eq., 1.2 g). The solvent was changed to ethanol by vacuum distillation at a pressure of 250-300 hPa (250-300 mbar) and at 70 °C. Then, water was added to the distillation residue at 60-70°C. After the addition, the mixture was further stirred at 60-70°C for 1 hour, cooled to 25°C over a period of 3 hours, and finally stirred again at 25°C for another 2 hours. The reaction mixture was filtered, washed with 50% ethanol solution and dried in vacuo at 85 °C to give compound D7 as a white solid (65.7 g, 97% yield, 1 H-NMR, 400 MHz, CDCl3: see Figure 4).

Example 2: Coupling stage (D7->D9)

A suspension of boronic acid D8 (10.40 g, 1.375 eq.) and potassium fluoride (KF, 9.37 g, 4 eq.) in 77 ml of water was heated to 35 °C in order to obtain a solution transparent. A reactor was charged under Argon atmosphere with Bromide D7 (20.00 g, 1.00 eq.), 12 ml of water and 140 ml of 1,4-dioxane. The mixture was refluxed and Pd(dppf)Cl ² (1.475 g, 0.05 eq.) was added. The aqueous D8/KF solution was added over 75 min and the reaction monitored by HPLC. The 1,4-dioxane was removed by distillation at 300-400 hPa (300-400 mbar). During distillation 150 ml of water was added, then 250 ml of ethyl acetate was added and a biphasic mixture was obtained. The phases were separated and the organic layer was extracted with 100 ml of semi-concentrated brine. Ethyl acetate was removed by distillation. To the resulting brown suspension, 200 ml of ethanol was added. The solvent was removed by distillation keeping the volume constant by adding 100 ml of ethanol. After the solvent change was completed, the mixture was cooled to 0 °C in 60 min. Seed crystals obtained in a previous reaction were added. The mixture was stirred for 60 min at 0°C and the product was collected by filtration. The product was dried in vacuo at 55°C to obtain the compound of formula D9 (Yield approx. 75%, 1H-NMR, 400 MHz, d6-DMSO: see Figure 5).

Example 3: Separation of stereoisomers-(D9->D10+D14) and (D14->D9->D10+D14)

A solution of L-malic acid (7.10 g, 1 eq.) was prepared in 100 mL of ethyl acetate at 70 °C and stored at 50 °C until further use. A reactor was charged with compound D9 (30.00 g, 1.00 eq.) and 1000 ml of ethyl acetate. 10.00 g of water was added and the mixture was stirred under reflux. The remaining residue was removed by filtration. The reactor was charged with the solution of compound D9 in ethyl acetate and the solution of L-malic acid. Then, the water was removed by azeotropic distillation. During distillation, the volume was kept constant. At the end of the distillation, the mixture is cooled to 20 °C. In case no crystals are formed, seed crystals, obtained in a previous reaction, can be added as an option. In order to remove sludge from the reactor wall, the mixture was heated to reflux and then cooled to 20°C. The product, D10 L-malic acid, was collected by filtration and dried in vacuo at 50°C (42% yield, 1H-NMR, 400 MHz, d6-DMSO: see Figure 6).

The reactor was charged with the mother liquor and the solvent was removed by distillation. The organic layer was extracted with water. The solvent was changed to ethanol and, if necessary, seed crystals of compound D14, obtained in a previous reaction, were added. The mixture was cooled to 5°C. Compound D14 was collected by filtration and dried in vacuo at 50°C to obtain compound D14 (47% Yield, 1 H-NMR, 400 MHz, d6-DMSO: see Figure 7).

Then a solution of compound D14 (40.00 g, 1.00 eq.) in 800 mL of methanol was stirred at 65 °C for 15 min, followed by the addition of 2.5% aqueous NaHCO3 solution ( 44.5 g, 0.2 eq.). The reaction mixture was stirred for 24 hours at 65 °C and the racemization or formation of compound D9 was monitored by HPLC. The reaction mixture was then cooled to 22 °C and neutralized with sulfuric acid (3.38 g, 0.1095 eq.). The mixture was filtered over a filter cap and the solvent was removed. Ethanol was added and the mixture was cooled to 0°C and stirred for 2 hours. The product was collected by filtration, washed twice with ethanol and dried under vacuum at 50°C to finally be used to produce L-malic acid compound D10 according to the procedure described above.

Example 4: Formation of hydrate (D10->D12)

A reactor was charged with 1.5 g of L-malic acid compound D10 and the solid dissolved in acetone (8.8 ml). The resulting solution was filtered at 25°C and the filter washed with acetone (2.5 ml). Then, water (12.5 ml) at 25 °C was added to the solution in 1 hour. To the resulting mixture, 2 mg of seed crystals of hydrate D12 were added. Further water (26.3 mL) was then added over 1 hour to the reaction mixture and the reaction was stirred at 25°C for 4 hours. The resulting suspension was isolated via filtration and the filter cake washed with 2 x 7.5 mL of 25°C water. Finally, the product was vacuum dried at 35 °C and 35 hPa (35 mbar) for about 15 hours to give the hydrated compound D12 (1.4 g).

Example 5: Formation of ethanol solvate (D10->D11)

A reactor was charged with L-malic acid compound D10, (15.0 g, 1.00 eq.), ethyl acetate (300 mL), and water (75 mL). The suspension was heated to 50 °C and stirred until a clear biphasic solution was obtained. The reaction mixture was then cooled to 25°C to separate the organic/aqueous layers, and the aqueous layer was removed. Then water (75 ml) was added and the mixture was stirred, these steps were repeated twice. Finally, the organic layer was filtered in order to obtain a clear solution. The solvent was removed by distillation and replaced with ethanol. Solvent was removed to final volume (75 ml), the mixture was cooled to 5 °C and further stirred. The product was collected by filtration and dried under vacuum at 50 °C to obtain compound D11 as ethanolate (ethanol solvent) in 90% yield.

1H-NMR (400 MHz, DMSO-d6) delta ppm: 0.53 (d, J=6.78 Hz, 3H) 1.06 (t, J=6.90 Hz, 3H) 1.34 (d, J=6.78 Hz, 3H) 3.37 3.53 (m, 5H) 3.95 (s, 3H) 3.99 (s, 3H) 4.05-4.18 (m, 1H) 4, 34 (t, J=5.02 Hz, 1H) 6.73 (s, 1H) 7.33 (brd, J=8.28 Hz, 2H) 7.43 (d, J=7.90 Hz, 2H) 7.51 (d, J=2.76 Hz, 1H) 7.93 (d, J=2.76. 1H) 8.50 (s, 1H).

Claims (4)

1. A process for preparing a compound of formula (D7), or a salt thereof, or a solvate thereof,

comprising the step of reacting a compound of formula (D6), or a salt thereof, or a solvate thereof,

in a solvent in the presence of base and a coupling agent, wherein the coupling agent is N,N'-carbonyldiimidazole. 2. The process according to claim 1, wherein the solvent is one or more polar solvents selected from tetrahydrofuran, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, dichloromethane, acetonitrile, ethyl acetate and ethanol. 3. The process according to one of the preceding claims, wherein the base is one or more bases selected from fBuOK, LiHMDS, NaHMDS, MeONa, EtONa, fBuONa, K ² CO ³ , Cs ² CO ^a , K ³ PO ⁴ , DMAP, KOMe and KOEt, preferably the base is tBuOK. 4. The process according to claim 1, wherein the solvent is THF, the base is tBuOK, the coupling agent is N,N'-carbonyldiimidazole (CDI).

i. preparing a compound of formula (D7), or a salt thereof, or a solvate thereof, according to any one of claims 1 to 4, ii. preparing a compound of formula (D9), or a salt thereof, or a solvate thereof,

with a boronic acid of formula (D8),

in a solvent in the presence of a metal catalyst, a base and optionally a ligand, wherein the solution of

process that includes (a) reacting a compound of formula (D9), or a salt thereof, or a solvate thereof, in a solvent with an acid to obtain a mixture of a compound of formula (D14), or a salt thereof, or a solvate thereof, and compound of formula (D10) and optionally comprising the further steps of (b) reacting (D14), or a salt thereof, or a solvate thereof, to obtain a compound of formula (D9), or a salt thereof, or a solvate thereof, in a solvent in the presence of a base; Y (c) reacting compound of formula (D9), or a salt thereof, or a solvate thereof, in a solvent in the presence of an acid to obtain compound (D10); and, optionally, repeating steps of (b) and (c) at least once, and IV. reacting the compound of formula (D10) to obtain a compound of formula (I), or a solvate including a hydrate thereof, or a co-crystal thereof.